The potential to modulate the electrophysiological response of excitable cells (such as neurons and muscle cells) could potentially lead to treatment of neuromuscular conditions, pain, and other disorders associated with the activity of such cells. However, the administration of ligands that act on endogenous ion channels poses significant hurdles because of the potential for widespread side effects due to systemic delivery. Moreover, agents that act locally (such as silver or capsaicin) have unwanted side effects and can potentially cause permanent damage.
Modulation of neuronal activity by expression of a ligand-gated anionic channel has been shown previously wherein expression of a glutamate-gated chloride channel (GluCl), a nicotinicoid family receptor found in invertebrates, was used to silence neurons (Slimko et al., J. Neurosci., 22, 7373-9 (2002)). GluCl could be selectively activated by the addition of ivermectin, a high-potency ligand that has little or no effects on endogenous mammalian ion channels at low concentrations. For use in vertebrates, and particularly in human patients, however, this approach poses a risk of generating an immune response against such a foreign protein, leading to potential autoimmune disorders. Accordingly, additional methods and reagents for modulating the electrophysiological activity of excitable cells are desired.